PROJECT SUMMARY A single injection of small dose of ketamine induced a rapid resolution of suicidal ideation. Since acute ketamine effects are short lived, recent clinical studies are testing whether subchronic treatments with ketamine can prevent relapse to depression. The results of these studies are promising as they clearly show that repeated ketamine infusions achieved superior outcome when compared to acute treatment. It is clear therefore that the viability of ketamine as an antidepressant treatment will necessitate repeated infusions of small doses under a chronic regimen. The safety of such treatments is still not very clear when one acknowledges that ketamine is considered a drug of abuse. Furthermore, the comorbidity of depression with other drugs of abuse, especially alcohol adds further complications to the viability of ketamine as a treatment for depression. Finally, the effects of ketamine in both sexes are still understudied. The ketamine doses that are used to treat Treatment Resistant Depression [TRD] in humans work for both sexes and, so far, there were no efforts made to examine the antidepressant effects of lower doses of ketamine in women. This is despite some evidence in humans showing that ketamine use leads to severe cognitive impairments in women when compared to men and some evidence in rodents, showing higher sensitivity of female rodents to the analgesic and the antidepressant effects of ketamine. In rodents, ketamine also leads to greater neurotoxicity in females when compared to males. Accordingly, it is critical that further clinical and preclinical studies examine the safety of repeated treatments with low doses of ketamine, in both sexes, before approving ketamine as a safe treatment for TRD. Through this application we shall answer very specific questions about the safety of long term treatment with ketamine: 1- In both sexes, do repeated treatments with low doses of ketamine induce addictive-like behaviors? 2- Does female hormonal status play a role in response to ketamine's addictive properties?; 3- Does alcohol abuse enhance the addictive properties of ketamine in either sex? 4- What are the physiological adaptations that occur in the brain with repeated ketamine treatments? We truly believe that the response to these questions will inform clinicians about the safety or not of chronic ketamine treatment for TRD.